In this project we seek to advance understanding of the role of corticotropin releasing hormone (CRH) in normal and stress physiology and in disorders of hypothalamic-pituitary-adrenal function. Rapid progress in this area has been made possible by the recent discovery of the chemical structure of ovine CRH. Our objectives have been to determine the dose-response relationship for CRH in primates and in humans, to study the metabolic clearance rate of CRH in primates and in man, to develop methods to measure CRH accurately in tissue and in biological fluids, to measure CRH in the plasma and cerebrospinal fluid of patients with abnormalities of the hypothalamic-pituitary-adrenal axis, to develop a clinical CRH test and to evaluate its usefulness in adrenal insufficiency, Cushing's syndrome, and pseudo-Cushing's states. Our studies to date have shown that CRF is active in primates and man. The appropriate dose and mode of testing men have been established and the pharmacological parameters have been determined in both primates and men. CRH stimulation appears to be a good test in the differential diagnosis of adrenal insufficiency, Cushing's syndrome and pseudo Cushing's states. Physiological experiments suggest that Cushing's disease is pituitary whereas hypercortisolism in depression is hypothalamic in origin. Successful treatment of Cushing's disease with surgery is followed by normalization of the CRF stimulation test.